Those assigned to 4 weeks on the "low" diet in the 47-person trial showed a 0.34-log decline in lipid-depleted, 42-mer beta-amyloid (AB42) in cerebrospinal fluid (CSF), whereas participants eating foods high in fat and with a high glycemic index had a 0.5-log increase (P=0.01), according to Suzanne Craft, PhD, of Wake Forest University in Winston-Salem, N.C., and colleagues.

A similar but smaller difference in lipid-depleted, 40-mer beta-amyloid (AB40) that failed to reach statistical significance (P=0.15) was seen as well, the researchers reported online in JAMA Neurology.

In addition, the decreases in lipid-depleted beta-amyloid levels in participants on the "low" diet were associated with healthy increases in CSF insulin levels, Craft and colleagues indicated.

The researchers concluded that these effects of diet on lipid-depleted beta-amyloid "may be one of the mechanisms for how diets impart Alzheimer's disease risk or protection."

In an accompanying editorial, Deborah Blacker, MD, ScD, of Massachusetts General Hospital in Boston, noted that the study did not address whether the biochemical changes would have a clinical effect.

"The specifics of their model may not capture the real underlying biological effect of these diets, and it is unclear whether the observed changes in the intermediate outcomes would lead to beneficial changes in oligomers or plaque burden, much less to decreased brain atrophy or improved cognition," Blacker wrote.

She added that the study had no immediate clinical implications. In an interview with MedPage Today, Blacker noted that patients are already counseled to eat diets low in fats and with low glycemic index.

Nevertheless, Blacker said, the study is important in showing that dietary changes can affect amyloid chemistry in the brain, potentially a step toward solving the puzzle of Alzheimer's disease etiology.

But the causal links, if any, have been harder to establish. Such studies were unable to rule out the possibility that diet and diabetic status were simply markers for other, less obvious factors that influence risk of Alzheimer's disease.

In the study, Craft and colleagues recruited 20 cognitively normal older individuals and 27 with mild cognitive impairment. Their mean ages were 69 and 67, respectively.

Participants were assigned to one of two diets for 4 weeks: the "low" diet, with 25% of calories from fat and a glycemic index of less than 55; or a "high"diet, which had 45% of calories from fat and a glycemic index greater than 70. Diets were constructed to provide equal total caloric content as well as adequate overall macronutrient amounts.

CSF samples were taken at baseline and after the 4-week intervention. Levels of total and lipid-depleted apolipoprotein E (apoE) and AB40 and AB42 peptides, as well as insulin, were measured.

Levels of both forms of lipid-depleted beta-amyloid were higher at baseline in participants with mild cognitive impairment (MCI) compared with the cognitively normal individuals, with the difference in lipid-depleted AB40 reaching statistical significance (natural log pg/mL 8.74 in the MCI group versus 8.44 in the cognitively normal group, P=0.01).

APOE genotype was a strong influence on baseline values as well. Those positive for the epsilon-4 allele showed higher levels of lipid-depleted AB40, AB42, and apoE.

Craft and colleagues wrote that these findings helped to confirm the pathological nature of these lipid-depleted peptides, insofar as higher levels of lipid-depleted beta-amyloid proteins were associated increased cognitive impairment. The increase in these proteins in participants with the epsilon-4 APOE genotype, the most powerful known risk factor for Alzheimer's disease, provides further support for the connection, the researchers suggested.

In addition to showing presumably beneficial changes in lipid-depleted AB40 and AB42 after 4 weeks on the "low" diet, the study also found similarly beneficial changes in CSF insulin.

Limitations to the study cited by the authors included its small size and short duration. Also, because both fat and carbohydrate content were manipulated in the diets, it was unclear whether one or the other was primarily responsible for the effects seen.

The study was funded by the National Institutes of Health, the Department of Veterans Affairs, and the Nancy and Buster Alvord Endowment.

Study authors and the editorialist declared they had no relevant financial interests.

John Gever, Managing Editor, has covered biomedicine and medical technology for more than 30 years. He holds a B.S. from the University of Michigan and an M.S. from Boston University. He is now based in Pittsburgh. In addition to his administrative duties, he covers neurology and psychiatry for MedPage Today.

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